Novel combined variants of LDLR and LDLRAP1 genes causing severe familial hypercholesterolemia

Alnouri, Fahad; Athar, Mohammad; Al-Allaf, Faisal A.; Abduljaleel, Zainularifeen; Taher, Mohiuddin M.; Bouazzaoui, Abdellatif; Ammari, Dalal Al; Karrar, Hussam; Albabtain, Monirah A

doi:10.1016/j.atherosclerosis.2018.06.878

Cited by 16 publications

(5 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Best practice in precision medicine requires that the diagnosis of FH be confirmed genetically [41]. Several countries have therefore undertaken their own genetic studies, supported in some cases by international experts [11,16,31,33,37,[42][43][44][45]. Genetic testing is important in countries with high rates of consanguinity [42].…”

Section: Genetic Testingmentioning

confidence: 99%

“…Several countries have therefore undertaken their own genetic studies, supported in some cases by international experts [11,16,31,33,37,[42][43][44][45]. Genetic testing is important in countries with high rates of consanguinity [42]. Next generation sequencing permits the detection of a wider spectrum of mutations [11,16,44,45] that not only facilitate a definitive diagnosis of FH, but may also confirm polygenic hypercholestrerolaemia; this molecular diagnosis may predict a more adverse prognosis in FH or when isolated may be used to ration cascade testing [46].…”

Section: Genetic Testingmentioning

confidence: 99%

See 1 more Smart Citation

Improving the global care of familial hypercholesterolaemia: Starting the ball rolling

Ray

Watts

2018

Atherosclerosis

View full text Add to dashboard Cite

Section: Genetic Testingmentioning

confidence: 99%

Section: Genetic Testingmentioning

confidence: 99%

Improving the global care of familial hypercholesterolaemia: Starting the ball rolling

Ray

Watts

2018

Atherosclerosis

View full text Add to dashboard Cite

“…FH can be heterozygous (frequently less severe, due to a single mutated allele) or homozygous (commonly severe, due to mutations in both alleles). Less commonly, FH can also be double heterozygous (two different mutated alleles at two separate genetic loci) or compound heterozygous (two different mutated alleles at one particular gene locus) [ 3 , 4 ]. In most studied populations, heterozygous FH (HeFH) affects one in 200–500 persons.…”

Section: Introductionmentioning

confidence: 99%

Familial Hypercholesterolemia in the Arabian Gulf Region: Clinical results of the Gulf FH Registry

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background and aims Familial hypercholesterolemia (FH) is a common autosomal dominant disorder that can result in premature atherosclerotic cardiovascular disease (ASCVD). Limited data are available worldwide about the prevalence and management of FH. Here, we aimed to estimate the prevalence and management of patients with FH in five Arabian Gulf countries (Saudi Arabia, Oman, United Arab Emirates, Kuwait, and Bahrain). Methods The multicentre, multinational Gulf FH registry included adults (≥18 years old) recruited from outpatient clinics in 14 tertiary-care centres across five Arabian Gulf countries over the last five years. The Gulf FH registry had four phases: 1- screening, 2- classification based on the Dutch Lipid Clinic Network, 3- genetic testing, and 4- follow-up. Results Among 34,366 screened patient records, 3713 patients had suspected FH (mean age: 49±15 years; 52% women) and 306 patients had definite or probable FH. Thus, the estimated FH prevalence was 0.9% (1:112). Treatments included high-intensity statin therapy (34%), ezetimibe (10%), and proprotein convertase subtilisin/kexin type 9 inhibitors (0.4%). Targets for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol were achieved by 12% and 30%, respectively, of patients at high ASCVD risk, and by 3% and 6%, respectively, of patients at very high ASCVD risk (p <0.001; for both comparisons). Conclusions This snap-shot study was the first to show the high estimated prevalence of FH in the Arabian Gulf region (about 3-fold the estimated prevalence worldwide), and is a “call-to-action” for further confirmation in future population studies. The small proportions of patients that achieved target LDL-C values implied that health care policies need to implement nation-wide screening, raise FH awareness, and improve management strategies for FH.

show abstract

“…Being a chaperone protein, LDLRAP1 binds to LDLR and allows the internalization of the LDL‐LDLR complex through clathrin‐coated pit into basolateral surface of hepatocytes, which are then delivered into endosomes. The molecular defects in LDLRAP1 protein as a result of amino acid substitutions in LDLRAP1 protein might lead to the retention of LDLRs on the apical surface, and severely reduce LDL uptake, thereby decreasing the LDL‐cholesterol metabolism, as seen in FH patients . But, how the missense mutations inactivate the LDLRAP1 protein is not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into the coding region mutations of low‐density lipoprotein receptor adaptor protein 1 (LDLRAP1) linked to familial hypercholesterolemia

Shaik

Alqahtani

Nasser

et al. 2020

The Journal of Gene Medicine

View full text Add to dashboard Cite

Background: Familial hypercholesterolemia (FH) is a lipid disorder caused by pathogenic mutations in LDLRAP1 gene. The present study has aimed to deepen our understanding about the pathogenicity predictions of FH causative genetic mutations, as well as their relationship to phenotype changes in LDLRAP1 protein, by utilizing multidirectional computational analysis.Methods: FH linked LDLRAP1 mutations were mined from databases, and the prediction ability of several pathogenicity classifiers against these clinical variants, was assessed through different statistical measures. Furthermore, these mutations were 3D modelled in protein structures to assess their impact on protein phenotype changes.Results: Our findings suggest that Polyphen-2, when compared with SIFT, M-CAP and CADD tools, can make better pathogenicity predictions for FH causative LDLRAP1 mutations. Through, 3D simulation and superimposition analysis of LDLRAP1 protein structures, it was found that missense mutations do not create any gross changes in the protein structure, although they could induce subtle structural changes at the level of amino acid residues. Near native molecular dynamic analysis revealed that missense mutations could induce variable degrees of fluctuation differences guiding the protein flexibility. Stability analysis showed that most missense mutations shifts the free energy equilibrium and hence they destabilize the protein.Molecular docking analysis demonstrates the molecular shifts in hydrogen and ionic bonds and Van der waals bonding properties, which further cause differences in the binding energy of LDLR-LDLRAP1 proteins. Conclusions:The diverse computational approaches used in the present study may provide a new dimension for exploring the structure-function relationship of the novel and deleterious LDLRAP1 mutations linked to FH. K E Y W O R D Sdocking, familial hypercholesterolemia, LDLRAP1, molecular dynamics, protein modelling Noor A. Shaik and Faten Al-Qahtani contributed equally to this work.

show abstract

Novel combined variants of LDLR and LDLRAP1 genes causing severe familial hypercholesterolemia

Cited by 16 publications

References 29 publications

Improving the global care of familial hypercholesterolaemia: Starting the ball rolling

Improving the global care of familial hypercholesterolaemia: Starting the ball rolling

Familial Hypercholesterolemia in the Arabian Gulf Region: Clinical results of the Gulf FH Registry

Molecular insights into the coding region mutations of low‐density lipoprotein receptor adaptor protein 1 (LDLRAP1) linked to familial hypercholesterolemia

Contact Info

Product

Resources

About